WO2003063863A1

WO2003063863A1 - Antibacterial pharmaceutical composition

Info

Publication number: WO2003063863A1
Application number: PCT/CN2003/000102
Authority: WO
Inventors: Li Liu
Original assignee: Li Liu
Priority date: 2002-01-29
Filing date: 2003-01-29
Publication date: 2003-08-07
Also published as: TW200412849A

Abstract

This invention relates to a pharmaceutical composition having synergic antimicrobial effects. It comprises furbenicillin, its derivatives or their pharmaceutically accepted salts or hydrolysable in vivo esters, and β-lactamaes inhibitor tazobactam, its derivatives or their pharmaceutically accepted salts or hydrolysable in vivo esters. Weight ratios of furbenicillin, its derivatives or their salts or esters to tazobactam, its derivative or their salts and esters is 20:1-1:10, preferably 8:1-1:1. The antibacterial spectrum of the pharmaceutical composition is broader, the antimicrobial efficacy is stronger.

Description

Antibacterial combination drugs

The present invention relates to a synergistic antibacterial combination drug. More specifically, the present invention relates to a combination drug comprising furicillin, a furicillin derivative or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable hydrolyzable ester in vivo, and β-lactam As an active ingredient, the enzyme inhibitor tazobactam, tazobactam derivative, or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable ester that is easily hydrolyzed in the body as an active ingredient has a broader antibacterial spectrum and stronger antibacterial effect.

Background technique

Since the 1980s, due to the increased use and improper use of antibiotics, clinical resistance to bacteria has increased. For example, Streptococcus pneumoniae is an important pathogen that causes bacterial meningitis, otitis media, sepsis, and pneumonia. It is the main pathogen of out-of-hospital infections in children. It is also the first pathogen in the community of adults, especially the elderly (Musher DM. Clin Infect Dis, 1992; 14: 801-809. Nohynek H, et al. Am J Dis Chid, 1991; 145: 618-622. Marrie TJ. Clin Infect Dis, 1994; 18: 501-505). Because Streptococcus pneumoniae has developed resistance to penicillin and other β-lactam antibiotics, penicillin-resistant Streptococcus pneumoniae has been widely spread throughout the world since the 1990s, and the therapeutic effect of drugs has declined, endangering patients' lives.

Pseudomonas aeruginosa, also known as Pseudomonas aeruginosa, is a common pathogen of the most serious hospital-acquired infections. It is highly prone to acquire acquired drug resistance, and it is not easy to be killed by the respiratory defense mechanism, which makes clinical treatment difficult. The mortality rate of Pseudomonas aeruginosa pneumonia is as high as 30%, and the mortality rate of Pseudomonas aeruginosa septicaemia is as high as 80-90%. Pseudomonas aeruginosa is currently one of the most widespread and serious problems in nosocomial infections in hospitals. Therefore, the development of new highly effective anti-infective drugs is very urgent and important.

Furbenicillin (6- [D-a- (3- (2-furanyl) urea) phenylacetylamino] penicillanoic acid

(Furbenicillin) is a broad-spectrum semi-synthetic ureide penicillin with strong antibacterial properties. Activity against Gram-positive bacteria such as hemolytic streptococcus, Streptococcus grass greens, meningococcus, pneumococcus, enterococcus, influenzae bacillus, alcaligenes, proteus mirabilis, typhoid, paratyphoid, and pseudomonas And negative bacteria have broad antibacterial activity, high activity against Pseudomonas aeruginosa, and strong outer membrane penetration. It has been found in the studies of the protein affinity of flavicillin and other ureide penicillins, and other β-lactam antibiotics to E. coli K-12 and Pseudomonas aeruginosa K799 / WT PBPS that furacillin and two bacteria must be PBP is multi-site binding and has a strong binding effect. It has a high affinity for E. coli PB2 and PB3, and also has a strong affinity for E. coli PBPla and PBPlb. Among the ureide penicillins, aloxicillin is lethal to E. coli. The affinity of sexual PBP (PBPlb, PBP2, PBP3) is not as good as that of furicillin, while meloxicillin and piperacillin are not as good as those of furacillin, and they are not as good as those of furicillin, and PBP2 Affinity is better than piperacillin, and its affinity for PBP2 and PBP3 is significantly higher than that of third-generation cephalosporins such as cefoperazone. In terms of safety and effectiveness, ureide penicillins are the most valuable antibiotics against Pseudomonas aeruginosa. The WHO Expert Committee on Essential Medicines has listed ureide penicillins as essential medicines, mainly used for Pseudomonas aeruginosa infection (Li Jiatai, Chinese Journal of Internal Medicine 1989; 6: 332),

Furbenicillin (see, for example, Canadian Patent Can.966853, British Patent 1282742, US Patent 3479339) was synthesized by the United States Bristol-Myer Company in 1969, but has not been listed abroad, and it was the first to be marketed in China. As with most β-lactam antibiotics, furamycin also has the weakness of being unstable to β-lactamase, and its effect on some bacteria is still not strong enough.

Tazobactam and its derivatives are irreversible and competitive β-lactamase inhibitors developed by companies such as Taiho and other Japanese companies after 1985 (see, for example, U.S. Patent Nos. 4,562,073 and 5763603). Chromosomal or plasmid-mediated inhibition of β-lactamase. Tazobactam and its derivatives have only weak antibacterial activity, so they cannot be used alone as antibacterial drugs, mainly with β-lactam antibiotics. It is compatible with all kinds of severe infections and resistant strains. At present, a compound of tazobactam sodium and piperacillin (Tazocin) (1: 8) has been marketed. There is no report in the published literature on the synergistic effect of tazobactam combined with furfuricin.

The inventors of the present invention have conducted research on the combined use of furicillin and its derivatives with tazobactam and its derivatives, and found that furacillin, furacillin derivatives or pharmaceutically acceptable salts or pharmaceutically acceptable salts thereof Compatible esters that are readily hydrolyzed in the body, and beta-lactamase inhibitor tazobactam, tazobactam derivatives or pharmaceutically acceptable salts or pharmaceutically acceptable hydrolysable esters that are compatible in the body It can produce a synergistic effect, thereby providing a broader antibacterial spectrum and a stronger antibacterial effect. An antibacterial combination drug comprising a furicillin derivative and a tazobactam derivative can be used to treat bacterial infections in mammals. . The combined drug has a more prominent advantage than a single component, especially in the fight against pathogenic bacteria such as Streptococcus pneumoniae and Pseudomonas aeruginosa, that is, a significant synergistic effect, which is conducive to significantly improving the antibacterial effect of furicillin or its derivative .

Summary of the Invention

The present invention relates to the field of pharmaceutical technology, and in particular, to a ureide penicillin-containing furbenicillin, furbenicillin derivative or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable hydrolysable substance in vivo. An antibacterial combination drug with a beta-lactamase inhibitor tazobactam, a tazobactam derivative or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable hydrolyzable ester in vivo .

It is an object of the present invention to provide a combination medicine, which comprises a furicillin, a furicillin derivative or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, which is represented by the following formula (1): Hydrolyzed esters:

( 1)

Wherein, Ri, R _2, R ₃ may be the same or different, represent a hydrogen atom, a nitro group, di (D_ ₆ alkyl) amino, <_ ^ ₆ alkanoylamino group, an amino group, a hydroxyl group, <^ _ ₆ alkanoyloxymethyl Radical, d. ₆ alkyl, d_ ₆ alkoxy, sulfamoyl, chlorine, iodine, bromine, fluorine or trifluoromethyl,

Z represents d_ ₆ alkyl, C ₄ _ ₇ cycloalkyl, mono-substituted prime d_ ₆ alkyl, dichloromethyl, trichloromethyl, C ₂ _ ₆ alkenyl group, and the following groups:

In the formula, n is an integer from 0 to 3, R ₄ , 11 ₅ and 11 ₆ may be the same or different, and have the meanings of Ri, 11 ₂ and 11 ₃ described above, and

Tazobactam, a tazobactam derivative or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable hydrolysable ester in vivo represented by the following formula (2):

( 2 )

Wherein, R ₇ and R ₈ may be the same or different, and represent a hydrogen atom, a tri (d- ₆ alkyl) silyl group, a carboxyl group, or a carboxyl group forming a pharmaceutically acceptable salt, or an esterified carboxyl group, wherein the formula (1) A compound or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable hydrolyzable ester in vivo and a compound of formula (2) or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable hydrolyzable ester in vivo The weight ratio is 20: 1 to 1:10, preferably 8: 1 to 1: 1.

A pharmaceutically acceptable salt of a compound of formula (1) and / or a compound of formula (2) suitable for use in the present invention may be selected from alkali metal salts of the compound, such as potassium salts, sodium salts; alkaline earth metal salts, such as calcium salts , Magnesium salts; organic amine salts, such as salts of triethylamine, 2-hydroxyethylamine, procaine, etc .; basic amino acid salts, ammonium salts, and hydrates thereof. Alkali metal salts such as potassium salts and sodium salts are preferred.

A pharmaceutically acceptable ester of a compound of formula (1) and / or a compound of formula (2) suitable for use in the present invention is an ester that is easily hydrolyzed to a free acid in vivo. Examples of the furicillin derivatives that can be used in the combination medicine of the present invention include, but are not limited to: furicillin sodium, furicillin sodium dihydrate, furicillin potassium, furicillin potassium trihydrate, clofuricillin Alkali metal salts and their hydrates, bromofurin penicillin alkali metal salts and their hydrates.

According to a preferred embodiment of the present invention, the compound of the formula (1) which can be used in the present invention may be selected from the group consisting of free benzyl penicillin, furenicin sodium, furenicin sodium dihydrate, furenicin potassium, furenzin Penicillin potassium trihydrate.

According to a preferred embodiment of the present invention, in the compound of the above formula (2), one of R ₇ and R ₈ is a hydrogen atom, and the other is an esterified carboxyl group. Alternatively, in the compound of formula (2), and R ₂ are both esterified carboxyl groups. The esterified carboxyl group is preferably an alkoxycarbonyl group, and the alkyl portion has 1 to 18 carbon atoms.

According to a preferred embodiment of the invention, in formula (2) compounds, 1 ^ 1 and ₂ - of a hydrogen atom and the other is the formation of pharmaceutically acceptable salts of carboxy group.

According to another preferred embodiment of the present invention, in the compound of formula (2), one of 1 ^ and 11 ₂ is a tri (d- ₆ alkyl) silyl group.

Examples of tazobactam derivatives useful in the combination drugs of the present invention include, but are not limited to: tazobactam, tazobactam sodium, tazobactam potassium, tazobactam hemihydrate, and tazobactam Tantalum monohydrate.

According to a preferred embodiment of the present invention, the compound of formula (2) useful in the present invention may be selected from tazobactam acid, tazobactam sodium, tazobactam potassium, tazobactam hemihydrate and Tazobactam sodium monohydrate.

It has been found through research that when using benzyl penicillin or its derivative, adding a β-lactamase inhibitor, such as tazobactam or its derivative, which can effectively inhibit the effect of β-lactamase, is more beneficial Furacillin penicillin stably exerts its antibacterial effect and improves the stability to β-lactamase, so that the combined drug has a larger antibacterial spectrum and has a stronger antibacterial effect.

The combination drug of the present invention can be administered by various routes, such as enteral administration Such as oral administration, or parenteral administration such as intravenous injection, transdermal injection and so on. The combination medicament of the present invention may be administered in a single dose or multiple doses per day, for example, 2-3 doses per day. The administration amount of the combination medicine of the present invention varies according to the age of the subject to be administered, the disease condition, the symptoms to be treated, and the mode of administration. However, for patients weighing about 75 kg, the daily dose is typically about 2-9 grams.

The combination medicine of the present invention can be made into various dosage forms, such as powder injection, lyophilized powder injection, injection solution and the like. They can be prepared by techniques known in the art, such as common mixing, dissolving, and lyophilizing methods.

The combination medicine of the present invention may contain only the above-mentioned furbenicillin, a furfuricillin derivative or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable hydrolyzable ester in vivo, and a β-lactamase inhibitor tazobactam , Tazobactam derivative or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable ester which is easily hydrolyzed in vivo. Alternatively, in addition to the active ingredients, the combination medicament of the present invention also contains conventional pharmaceutical excipients or carriers. The selection of the type and amount of the excipient or carrier according to the dosage form of the combination drug is a well-known technique in the art.

For parenteral administration, the active ingredient of the combination drug of the present invention can be dissolved or dispersed in, for example, water for injection, an oily solvent such as a fatty oil, etc., to prepare a solution or a suspension. For intramuscular or intravenous application, it can be diluted with diluent (0.9% physiological saline for injection, sterile water for injection or 0.5% lidocaine hydrochloride), and then further diluted with 5% glucose solution or 0.9% physiological saline for injection.

In addition, the two active ingredients can also be filled in two different bottles to form a combined package, which exerts its synergistic effect in clinical treatment.

The antibacterial combination drug of furicillin and tazobactam is preferably administered clinically by injection, mainly by intravenous drip.

The antibacterial combination medicine provided by the present invention can be used to treat bacterial infections, such as respiratory infections, hepatobiliary infections, abdominal cavity infections, urinary tract infections, soft tissue and wound infections, pelvic infections, sepsis, meningitis, gynecological infections, bacterial infections, and Multiple microbial infections. The combination medicine of the invention is especially suitable for treating microbial infections sensitive to β-lactam antibiotics, and is also effective for some penicillin-resistant microorganisms. The combination medicine of the present invention can be used for the treatment of infectious diseases in humans, and also for the treatment of infectious diseases in animals. Very good antibacterial effect.

detailed description

The present invention will be further described in detail with reference to the following embodiments. It should be noted that these examples are merely illustrative of preferred embodiments of the present invention, and do not in any way limit the scope of the present invention.

Example 1: A combined preparation was prepared from 1 g of furbenicillin sodium and 1 g of tazobactam sodium monohydrate, and the powder injection preparation process was carried out.

Example 2: A combined preparation was prepared from 1 g of furbenicillin potassium trihydrate and 0.1 g of tazobactam sodium, which was performed according to the powder injection preparation process.

Example 3: A combined preparation is prepared from 1 g of furbenicillin potassium trihydrate and 1 g of tazobactam sodium, and is performed according to the powder injection preparation process.

Example 4: A combination preparation was prepared from 1 g of furbenicillin sodium and 0.125 g of tazobactam sodium, and the powder injection preparation process was carried out.

Example 5: A combined preparation was prepared from 2 g of furbenicillin sodium and 0.25 g of tazobactam sodium, and was performed according to the powder injection preparation process.

Example 6: A hydrazone combined preparation was prepared from 4 g of furicillin sodium and 0.5 g of tazobactam sodium, and the powder injection preparation process was performed.

Example 7: A combined preparation was prepared from 2 g of furicillin sodium and 0.5 g of tazobactam sodium, and the preparation process was performed according to a lyophilized powder injection preparation process.

Example 8: A combined preparation was prepared from 4 g of furbenicillin sodium and 1.0 g of tazobactam sodium, and the preparation process was performed according to a lyophilized powder injection preparation process.

Example 9: A combined preparation was prepared from 4 g of furbenicillin potassium trihydrate and 1 g of tazobactam sodium, and the preparation process was performed according to a lyophilized powder injection preparation process. Example 10: A combined preparation was prepared from 4 g of furbenicillin sodium and 1 g of tazobactam sodium monohydrate, and was performed according to a powder injection preparation process.

Example 11: A combined preparation was prepared from 1 g of furbenicillin sodium and 0.125 g of tazobactam hemihydrate, which was performed according to the powder injection preparation process.

Example 12: A combined preparation was prepared from 1 g of furbenicillin-bell trihydrate and 0.125 g of tazobactam sodium, which was performed according to the powder injection preparation process. The in vitro test of the antibacterial combination drug of the present invention using clinically isolated pathogenic bacteria has shown that its antibacterial effect is significantly enhanced than that of any single component, that is, it has a very obvious synergistic effect. The results of the in vitro tests are as follows:

Table 1 shows the results of the in vitro antibacterial test of the combination drug of the present invention (1: 1 composition of furfuricillin sodium and tazobactam sodium monohydrate) of Example 1.

Table 1. In vitro antibacterial activity of furicillin sodium and tazobactam sodium monohydrate composition (1: 1) (MIC ₅₀ mg / 1)

Bacteria (number of strains) Furicillin sodium tazobactam sodium monohydrate composition Streptococcus pneumoniae (5) 0.031 256 0.002 Table 2 shows the combination drug of the present invention (Furicillin potassium trihydrate and tazolium) according to Example 2 Results of in vitro antibacterial test of 10: 1 composition of Batam sodium.

Table 2. In vitro antibacterial activity of the combination of furicillin potassium trihydrate and tazobactam sodium (10: 1) (MICso mg / 1)

Bacteria (number of strains) Furoxicillin potassium trihydrate tazobactam sodium composition Streptococcus pneumoniae (5) 0.031 256 0.008 Table 3 shows the combination drug of the present invention (Furacillin potassium trihydrate and tazobazole) of Example 3 Results of in vitro antibacterial test of batam sodium (1: 1 composition).

Table 3. Compositions of furfuricin potassium trihydrate and tazobactam sodium (1: 1) in vitro antibacterial activity (MICso mg / 1)

Bacteria (number of strains) Furbenicillin potassium trihydrate tazobactam sodium composition Streptococcus pneumoniae (5) 0.031 256 0.002 Table 4 shows the results of the in vitro antibacterial test of the combination drug of the present invention (a 4: 1 composition of furbenicillin sodium and tazobactam sodium) according to Example 7.

Table 4. Compositions of furicillin sodium and tazobactam sodium (4: 1) in vitro antibacterial activity (MICso mg / 1)

Bacteria (number of strains) Furbenicillin sodium Tabatana composition Streptococcus pneumoniae (5) 0.031 256 0.004 Table 5 shows the combination drug of the present invention (Furacillin potassium trihydrate and tazobactam sodium of Example 9) 4: 1 composition) in vitro antibacterial test results.

Table 5. Compositions of furicillin potassium trihydrate and tazobactam sodium (4: 1) in vitro antibacterial activity (MICso mg / 1)

Bacteria (number of strains) Furoxicillin potassium trihydrate Tasalactam sodium composition Streptococcus pneumoniae (5) 0.031 256 0.004 Table 6 shows the combination drug of the present invention (Furacillin sodium and tazobactam sodium) of Example 10 Monohydrate composition (4: 1)) Results of in vitro antibacterial test.

Table 6. In vitro antibacterial activity of furicillin sodium and tazobactam monohydrate composition (4: 1) (MIC _5. mg / 1)

Bacteria (number of strains) Furacillin sodium tazobactam sodium monohydrate composition Streptococcus pneumoniae (5) 0.031 256 0.004 Table 7 shows the combination drug of the present invention (furacillin sodium and tazobactam half) in Example 11 Hydrate composition (8: 1)) in vitro antibacterial test results

Table 7. In vitro antibacterial activity of furicillin sodium and tazobactam hemihydrate composition (8: 1) (MIC _{5 ()} mg / l)

Bacteria (number of strains) Furacillin sodium tazobactam sodium monohydrate composition Streptococcus pneumoniae (5) 0.031 256 0.008 Table 8 shows the combination drug of the present invention (Furacillin potassium trihydrate) of Example 12 Compound and tazobactam sodium composition (8: 1)) in vitro antibacterial test results.

Table 8. Compositions of furicillin potassium trihydrate and tazobactam sodium (8:

External antibacterial activity (MIC _s. Mg / l)

Bacteria (number of strains) Furacillin sodium sodium tazobactam sodium monohydrate composition Streptococcus pneumoniae (5) 0.031 256 0.008 The results of an in vitro antibacterial test of zobactam sodium composition (8: 1)) with the active ingredient alone and ceftazidime.

Table 9. Comparison of antibacterial activity in vitro by combination of furicillin sodium and tazobactam sodium

(MIC ₅₀ mg / l)

Bacteria (number of strains) benzyl penicillin combination drug tasaltan ceftazidime

(Example 6)

Staphylococcus aureus (8) 0.5 0.125 128 32

Meningococcus (4) 0.031 0.008 256 0.016 Streptococcus pneumoniae (12) 0.031 0.008 128 0.5

Hemolytic streptococcus (14) 0.062 0.016 256 0.5

E. coli (18) 4 0.125 256 0.5

Klebsiella (11) 128 4 256 1

Pseudomonas aeruginosa (7) 4 2> 256 8

Influenza (12) 1 0.25> 256 0.5

Peperomia singularis (11) 8 0.25> 256 0.06

Clostridium cloacae (8) 16 2> 256 32

The in vitro antibacterial combination drug of the present invention has proved that its antibacterial activity and antibacterial activity are stronger than those of the compound of formula (1) or (2) when used alone.

In summary, there is a significant synergy between tazobactam or its derivative (2), the active ingredient of the combination drug according to the present invention and furazin or its derivative (1). The effect can obviously enhance the antibacterial activity of furicillin or its derivative, expand its antibacterial spectrum, and is conducive to enhancing the clinical efficacy of the drug and rejuvenating the old medicine with new youth.

The present invention has been described above with reference to preferred embodiments and examples. However, it should be understood that these implementations and examples are only for those skilled in the art to better understand the purpose, implementation and effect of the present invention, and are not intended to limit the scope of the present invention. After reading this specification, those skilled in the art can easily make various changes to the present invention without departing from the spirit and scope of the present invention. The invention is intended to include all such changes and modifications.

Claims

1. A combination drug comprising a furicillin, a furicillin derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable hydrolysable ester in vivo:

(1)

Wherein, R _2, R ₃ may be the same or different, represent a hydrogen atom, a nitro group, di (d_ ₆ alkyl) amino, d_ ₆ alkanoylamino group, an amino group, a hydroxyl group, Cn_ ₆ alkanoyloxy, d. ₆ alkoxy Radical, d- ₆ alkoxy, sulfamoyl, chlorine, iodine, bromine, fluorine or trifluoromethyl,

Z represents d_ ₆ alkyl, C ₄ _ ₇ cycloalkyl, halo-substituted mono d_ ₆ alkyl, dichloromethyl, trichloromethyl, c ₂ _ ₆ alkenyl group, and the following groups:

In the formula, n is an integer from 0 to 3, R ₄ , R ₅ and R ₆ may be the same or different, and have the meanings of Ri, R ₂ and R ₃ described above, and

Tazobactam, a tazobactam derivative or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable hydrolysable ester in vivo represented by the following formula (2):

( 2 )

Wherein, R ₇ and R ₈ may be the same or different and represent a hydrogen atom, a tris (d- ₆ alkyl) silyl group, a carboxyl group, or a carboxyl group or an esterified carboxyl group forming a pharmaceutically acceptable salt, wherein the formula (1 ) Furacillin, Furacillin derivative or a pharmaceutically acceptable salt or ester thereof with tazobactam, tazobactam derivative or a pharmaceutically acceptable salt or ester thereof of formula (2) The weight ratio is from 20: 1 to 1:10.

2. The combination drug according to claim 1, wherein the furicillin of formula (1), a furacillin derivative or a pharmaceutically acceptable salt or ester thereof, and tazobactam of formula (2), other The weight ratio of the zobactam derivative or a pharmaceutically acceptable salt or ester thereof is 8: 1 to 1: 1.

3. The combination drug according to claim 1, wherein the pharmaceutically acceptable salt of the compound of formula (1) and / or the compound of formula (2) is selected from an alkali metal salt, an alkaline earth metal salt, an organic amine salt, a base Amino acid salts, ammonium salts, and their hydrates.

4. The combination drug according to claim 1, wherein the compound of formula (1) can be selected from the group consisting of free furicillin, furicillin sodium, furicillin sodium dihydrate, furicillin potassium, and furicillin Potassium trihydrate.

5. The combination drug according to claim 1, wherein in the compound of formula (2), one of 1 ^ and 11 ₂ is a hydrogen atom, and the other is an esterified carboxyl group.

6. The combination drug according to claim 1, wherein in the compound of formula (2), and 11 ₂ are both esterified carboxyl groups.

7. The combination drug according to claim 1, wherein in the compound of formula (2), and 11 ₂ are a hydrogen atom, and the other is a carboxyl group forming a pharmaceutically acceptable salt.

The combination drug according to claim 1, wherein in the compound of formula (2), one of Ri and R ₂ is a tri (Cw alkyl) silyl group.

The combination drug according to claim 1, 5 or 6, wherein the esterified carboxyl group is an alkoxycarbonyl group, and the alkyl portion has 1 to 18 carbon atoms.

10. The combination drug according to claim 1, wherein the compound of formula (2) can be selected from tazobactam, tazobactam sodium, tazobactam potassium, tazobactam hemihydrate, and tazobactam Tantalum monohydrate.